The name of this program changed this year from the NIH Chemical Genomics Center (NCGC) to the Molecular Libraries Probe Production Centers Network (MLPCN) because the MLPCN was transferred from the NIH Common Fund to NCATS. The NCGC activities, which NCATS reported last year, were part of the MLPCN and are included in the MLPCN activities. During the reporting year, the MLPCN worked with over 300 researchers worldwide to advise them on assay design and development, chemistry research, informatics research, technology development projects, and to run high-throughput screens and chemically optimize small molecule leads. In collaboration with the the U.S. Environmental Protection Agency (EPA), the National Toxicology Program (NTP), NIEHS, FDA, NCI, numerous rare disease foundations, and other intramural and extramural laboratories, the MLPCN performed over 31 high-throughput screens on molecular targets and cellular phenotypes important for virtually every area of biology and disease. In order to validate data, we have also deposited 48 hit validation assays and 37 SAR assays in PubChem. The MLPCN also continued its work in the field of siRNA, initiating assay development on 14 projects, completing 18 pilot screens (1,000 genes), and completing 18 primary screens (22,000 genes), and moving into hit validation and follow-up on those projects. 10 new chemical probes of diverse biologies were discovered, and MLPCN scientists published 47 peer reviewed publications during FY14, including 8 high impact publications. The MLPCN filed 3 patent applications during this reporting period. Also during the reporting period, MLPCN deposited a total of 1.28 billion data points into PubChem. MLPCN has deposited 188,906 Substance Identifications and 1,326 Assay Identifications into PubChem. MLPCN continued to apply its chemistry expertise to optimizing probes; a portfolio of 19 in-house chemistry projects and 18 chemistry collaborations was maintained throughout the year. Under leadership from MLPCN, the EPA, and the NTP of NIEHS, Tox21 continued to flourish. Tox21 is an initiative designed to predict the toxicity of chemicals on human health and the environment. This is accomplished by developing in vitro assays for more predictive, mechanistically-based methods than those used with current animal testing. During FY14, Tox21 continued its accelerated production phase. In the current reporting year, MLPCN completed 8 full Tox21 screens and 6 online validation studies. Also, 11 smaller-scale screens, including fruit and vegetable extracts, were analyzed in addition to 17 follow-up experiments on specific, varied cell lines. In FY14, the drug combination program finalized several projects and initiated several new and exciting programs in diverse areas of biology including Malaria, Ewings Sarcoma and the rare pediatric cancer Diffuse Intrinsic Pontine Glioma (DIPG). Novel findings are being examined in advanced preclinical models with high hopes of human clinical trials not far behind. A total of 8 new projects were initiated, 4 of which have come to completion. The support of the NCI Major Opportunities Award and the collaborative strength of many intramural NIH investigators and extramural scientists have made many of these efforts possible. The Assay Guidance manual has continued to evolve and has become a central resource for academic and industrial investigators interested in MLPCN science. With its wide-ranging audience it continues to be a valuable resource that is free and easily accessible. The manual is published as an eBook on the NLM/NCBI site (http://www.ncbi.nlm.nih.gov/books/NBK53196/). In the reporting period, 79,578 unique IP addresses accessed the book. This indicates that a large number of new users are finding the Assay Guidance Manual site useful in early drug discovery and translational science applications. The manual remains a central resource for investigators interested in translational sciences and applying concepts within their own study. Given the MLPCN's continual efficiency improvement program, we were able to increase the throughput of existing robotic screening, informatics, and chemistry systems by improvements in applications, software, and utilization scheduling, driven by both the project teams and Project Management. The MLPCN maintained its existing robotic technology and Bio Safety Levels 1, 2, and 3 facilities during the reporting period. The MLPCN's Outreach program continued its extraordinary record of productivity during the reporting period. MLPCN staff advised 166 outside investigators on assay design and assay development, and with chemistry, informatics, and technology development inquiries. MLPCN scientists gave 50 invited presentations throughout the U.S., Europe, and Asia during the period. MLPCN outreach resulted in the submission of over 68 grant applications for NIH programs. The Assay Guidance manual has continued to evolve and has become a central resource for investigators interested in MLPCN science. During the year, the MLPCN also maintained its status as an active member of the NCI's Chemical Biology Consortium. It currently has two active projects in collaboration with the NCI program, has recently presented one more. NCI has also inquired about the possibility of presenting one further project of interest. Finally, MLPCN's work on its IATAP grants continued.